The invention relates to substituted propanolamine derivatives and to their acid addition salts.
Several classes of active substances for the treatment of obesity and disorders of lipid metabolism have already been described:
polymeric adsorbers such as, for example, cholestyramine,
benzothiazepines (WO 93/16055),
bile acid dimers and conjugates (EP 0 489 423) and
4-amino-2-ureidopyrimidine-5-carboxamides (EP 0 557 879).
The invention was based on the object of providing further compounds which have a therapeutically exploitable hypolipidemic effect.
The invention therefore relates to propanolamine derivatives of formula I 
in which
R1 is phenyl, or heteroaryl, which is unsubstituted or optionally substituted by one to three independent radicals, it being possible for the aromatic or heteroaromatic ring to be mono- to trisubstituted by fluorine, chlorine, bromine, iodine, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(C1-C8)-alkoxy, xe2x80x94(C1-C8)-alkyl, xe2x80x94NH2, xe2x80x94NHxe2x80x94R9, xe2x80x94N(R9)R10, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOR11, xe2x80x94(Cxe2x95x90O)xe2x80x94R12, xe2x80x94(C1-C6)-alkyl-OH, xe2x80x94(C1-C6)-alkyl(xe2x80x94OH)-phenyl, xe2x80x94(C1-C6)-alkyl-CF3, xe2x80x94(C1-C6-alkyl-NO2, xe2x80x94(C1-C6)-alkyl-CN, xe2x80x94(C1-C6)-alkyl-NH2, xe2x80x94(C1-C6)-alkyl-NHxe2x80x94R9, xe2x80x94(C1-C6)-alkyl-N(R9)R10, xe2x80x94(C1-C6)-alkyl-CHO, xe2x80x94(C1-C6)-alkyl-COOH, xe2x80x94(C1-C6)-alkyl-COOR11, xe2x80x94(C1-C6)-alkyl-(Cxe2x95x90O)xe2x80x94R12, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-OH, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-CF3, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-NO2, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-CN, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-NH2, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-NHxe2x80x94R9, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-N(R9)R10, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-CHO, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-COOH, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-COOR11, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-(Cxe2x95x90O)xe2x80x94R12, xe2x80x94Nxe2x80x94SO3H, xe2x80x94SO2xe2x80x94CH3, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl-phenyl, (C1-C6)-alkylthio, or pyridyl, it being possible for one or more hydrogen(s) in the alkyl radicals to be replaced by fluorine and it being possible for phenyl and pyridyl, in turn, to be monosubstituted by methyl, methoxy or halogen;
R2 is H, xe2x80x94OH, xe2x80x94CH2OH, xe2x80x94OMe, xe2x80x94CHO, or xe2x80x94NH2;
R3 is a sugar residue, disugar residue, trisugar residue, tetrasugar residue, it being possible for the sugar residue, disugar residue, trisugar residue or tetrasugar residue to be optionally mono- or polysubstituted by one of the sugar protective groups, HOxe2x80x94SO2xe2x80x94, or (HO)2xe2x80x94POxe2x80x94;
R4 is H, methyl, F, or xe2x80x94OMe;
R9 to R12 each independently of one another is H or xe2x80x94(C1-C8)-alkyl;
Z is xe2x80x94NHxe2x80x94(C0-C16)-alkyl-Cxe2x95x90Oxe2x80x94, xe2x80x94Oxe2x80x94(C0-C16)-alkyl-Cxe2x95x90Oxe2x80x94, xe2x80x94(Cxe2x95x90O)mxe2x80x94(C1-C16)-alkyl-(Cxe2x95x90O)n, amino acid residue, diamino acid residue, it being possible for the amino acid residue or diamino acid residue optionally to be mono- or polysubstituted by an amino acid protective group, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically tolerated salts and physiologically functional derivatives.
Preferred compounds of formula I are those in which one or more radical(s) has, or have, the following meaning:
R1 is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthaliminyl, quinoyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or their benzo-fused derivatives, it being possible for the aromatic or heteroaromatic ring to be mono- to trisubstituted by fluorine, chlorine, bromine, iodine, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(C1-C8)-alkoxy, xe2x80x94(C1-C8)-alkyl, xe2x80x94NH2, xe2x80x94NHxe2x80x94R9, xe2x80x94N(R9)R10 , xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOR11, xe2x80x94(Cxe2x95x90O)xe2x80x94R12, xe2x80x94(C1-C6)-alkyl-OH, xe2x80x94(C1-C6)-alkyl(xe2x80x94OH)-phenyl, xe2x80x94(C1-C6)-alkyl-CF3, xe2x80x94(C1-C6)-alkyl-NO2, (C1-C6)-alkyl-CN, xe2x80x94(C1-C6)-alkyl-NH2, xe2x80x94(C1-C6)-alkyl-NHxe2x80x94R9, xe2x80x94(C1-C6)-alkyl-N(R9)R10, xe2x80x94(C1-C6)-alkyl-CHO, xe2x80x94(C1-C6)-alkyl-COOH, xe2x80x94(C1-C6)-alkyl-COOR11, xe2x80x94(C1-C6)-alkyl-(Cxe2x95x90O)xe2x80x94R12, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-OH, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-CF3, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-NO2, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-CN, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-NH2, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-NHxe2x80x94R9, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-N(R9)R10, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-CHO, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-COOH, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-COOR11, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-(Cxe2x95x90O)xe2x80x94R12, xe2x80x94Nxe2x80x94SO3H, xe2x80x94SO2xe2x80x94CH3, xe2x80x94Oxe2x80x94(C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl-phenyl, xe2x80x94(C1-C6)-alkylthio, pyridyl, it being possible for one or more hydrogen(s) in the alkyl radicals to be replaced by fluorine and it being possible for phenyl and pyridyl, in turn, to be monosubstituted by methyl, methoxy or halogen;
R2 is H, xe2x80x94OH, xe2x80x94CH2OH, xe2x80x94OMe, xe2x80x94CHO, or xe2x80x94NH2;
R3 is a sugar residue, disugar residue, trisugar residue, tetrasugar residue, it being possible for the sugar residue, disugar residue, trisugar residue or tetrasugar residue to be optionally mono- or polysubstituted by a sugar protective group, HOxe2x80x94SO2xe2x80x94, or (HO)2xe2x80x94POxe2x80x94;
R4 is H, methyl, F, or xe2x80x94OMe;
R9 to R12 each independently of one another is H, or xe2x80x94(C1-C8)-alkyl;
Z is xe2x80x94NHxe2x80x94(C0-C16)-alkyl-Cxe2x95x90Oxe2x80x94, xe2x80x94Oxe2x80x94(C0-C16)-alkyl-Cxe2x95x90Oxe2x80x94, xe2x80x94(Cxe2x95x90O)mxe2x80x94(C1xe2x80x94C16)-alkyl-(Cxe2x95x90O)n, an amino acid residue, a diamino acid residue, it being possible for the amino acid residue or the diamino acid residue optionally to be mono- or polysubstituted by an amino acid protective group, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically tolerated salts and physiologically functional derivatives.
Especially preferred compounds of formula I are those in which one or more radical(s) has, or have, the following meaning:
R1 is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthaliminyl, quinoyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isthiazolyl, it being possible for the aromatic or heteroaromatic ring to be mono- or disubstituted by fluorine, chlorine, bromine, iodine, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94(C1-C8)-alkoxy, xe2x80x94(C1-C8)-alkyl, xe2x80x94(C3-C6)-cycloalkyl, xe2x80x94NH2, xe2x80x94CHO, xe2x80x94COOH, or OCF3;
R2 is H, xe2x80x94OH, xe2x80x94CH2OH, xe2x80x94OMe, CHO, or xe2x80x94NH2;
R3 is a sugar residue, a disugar residue, the sugar residue or disugar residue optionally being mono- or polysubstituted by one of the sugar protective groups, HOxe2x80x94SO2xe2x80x94, or (HO)2xe2x80x94POxe2x80x94;
R4 is H, methyl, F, or xe2x80x94OMe;
Z is xe2x80x94NHxe2x80x94(C0-C16)-alkyl-Cxe2x95x90Oxe2x80x94, xe2x80x94Oxe2x80x94(C0-C16)-alkyl-Cxe2x95x90Oxe2x80x94, xe2x80x94(Cxe2x95x90O)mxe2x80x94(C1-C16)-alkyl-(Cxe2x95x90O)n, or a covalent bond;
n is 0 or 1;
m is 0 or 1;
and their physiologically tolerated acid addition salts.
Very especially preferred compounds of formula I are those in which one or more radical(s) has, or have, the following meaning:
R1 is phenyl, thiazolyl, oxazolyl, isoxazolyl, it being possible for the aromatic or heteroaromatic ring to be mono- to disubstituted by fluorine, chlorine, bromine, or xe2x80x94(C1-C8)-alkyl;
R2 is H, xe2x80x94OH, xe2x80x94CH2OH, xe2x80x94OMe, xe2x80x94CHO, or xe2x80x94NH2;
R3 is 
the sugar residue optionally being mono- or polysubstituted by one of the sugar protective groups, or HOxe2x80x94SO2xe2x80x94;
R4 is H, methyl, F, or xe2x80x94OMe;
Z is xe2x80x94NHxe2x80x94(C6-C12)-alkyl-Cxe2x95x90Oxe2x80x94, xe2x80x94Oxe2x80x94(C6-C12)-alkyl-Cxe2x95x90Oxe2x80x94, or xe2x80x94(Cxe2x95x90O)mxe2x80x94(C6-C12)-alkyl-(Cxe2x95x90O)n;
n is 0 or 1;
m is 0 or 1;
and their physiologically tolerated acid addition salts.
In the abovementioned heteroaryl groups, examples of suitable heteroatoms are O, S, and N.
Unless otherwise defined, heteroaromatic rings have 1-15 carbon atoms and 1-6 heteroatoms, preferably 1-5 carbon atoms and 1-2 heteroatoms.
Examples of the heteroaryl groups mentioned in the above definitions are thiophene, furan, pyridine, pyrimidine, indole, quinoline, oxazole, isoxazole, thiazole, or isothiazole.
The term alkyl is to be understood to mean straight-chain or branched hydrocarbon chains.
Sugar residues are to be understood to mean compounds derived from aldoses and ketoses having 3 to 7 carbon atoms, which can belong to the D- or L-series; they also include amino sugars, sugar alcohols or sugar acids. Examples which may be mentioned are glucose, mannose, fructose, galactose, ribose, erythrose, glycerinaldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, galactonic acid, mannonic acid, glucamine, 3-amino-1,2-propanediol, glucaric acid and galactaric acid.
Disugars are to be understood as meaning saccharides which are composed of two sugar units. Di-, tri-, or tetrasaccharides are the result of an acetal-like linkage of 2 or more sugars. The linkages may occur in the xcex1- or xcex2-form. Examples which may be mentioned are lactose, maltose and cellobiose.
If the sugar is substituted, then the substitution is preferably on the hydrogen atom of an OH group of the sugar.
The following protective groups are essentially suitable for the hydroxyl groups of the sugars: benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl, benzylidene, cyclohexylidene or isopropylidene protective groups.
The term amino acids or amino acid residues is to be understood as meaning the stereoisomeric forms, i.e., the D- or L-forms, of any of the following compounds:
The term amino-protective groups is to be understood as meaning suitable groups with which the functional groups of the side chains of the amino acid residues are protected (see, for example, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons, New York 1991). The following were typically used: t-butyloxy-carbonyl (BOC), 9-fluorenylmethoxy-carbonyl (Fmoc), benzyloxy-carbonyl (Z), 2xe2x80x94(3,5-dimethoxyphenyl)prop-2-yloxycarbonyl (Ddz), methyl, t-butyl, trityl, S-t-butyl.
Pharmaceutically tolerated salts are especially suitable for medicinal applications owing to the fact that their solubility in water is better than the original compounds, or basic compounds. These salts must have a pharmaceutically tolerated anion or cation. Suitable pharmaceutically tolerated acid addition salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and of organic acids such as, for example, acetic acid, benzene-sulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluene-sulfonic acid, tartaric acid and trifluoroacetic acid. The chloride salt is especially preferable for medicinal purposes. Suitable pharmaceutically tolerated basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
Salts with an anion which is not pharmaceutically tolerated also come within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically tolerated salts and/or for the use in nontherapeutic applications, for example, in vitro applications.
The term xe2x80x9cphysiologically functional derivativexe2x80x9d used herein designates any physiologically tolerated derivative of a compound of formula I according to the invention, for example an ester, which, upon administration to a mammal, such as, for example, humans, is capable (directly or indirectly) of forming a compound of formula I or an active metabolite thereof.
The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may be active themselves or not.
The compounds according to the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention come within the scope of the invention and are a further aspect of the invention.
All references to xe2x80x9ccompound(s) of formula (I)xe2x80x9d hereinbelow refer to a compound, or compounds, of formula (I) as described hereinabove and to their salts, solvates and physiologically functional derivatives as described herein.
The quantity of a compound of formula (I) required for the achievement of the desired biological effect depends on a series of factors, for example, the specific compound chosen, the desired use, the route of administration and the clinical condition of the patient. In general, the daily dose is from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of body weight, for example 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, 0.01 to 100 mg, typically 0.02 to 50 mg. In the case of pharmaceutically tolerated salts, the above weights relate to the weight of the aminopropanol ion derived from the salt. The compounds of formula (I) themselves can be used for prophylaxis or therapy of the abovementioned conditions in the form of a compound, but they are preferably present together with a tolerated excipient in the form of a pharmaceutical composition. Naturally, the excipient must be tolerated in the sense that it is compatible with the other components of the composition and is not harmful to the patient. The excipient can be a solid or a liquid or both and is preferably formulated together with the compound as a unit dose, for example a tablet which may contain 0.05% to 95% by weight of the active substance. Other pharmaceutically active substances may also be present, including other compounds of formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in mixing the components with pharmacologically tolerated excipients and/or auxiliaries.
Pharmaceutical compositions according to the invention are those which are suitable for oral and peroral (for example sublingual) administration, even though the most suitable route of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound used in each case. Sugar-coated formulations and sugar-coated slow-release formulations also fall within the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings encompass cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration can exist in separate units, for example capsules, wafers, lozenges or tablets, each of which contains a specific quantity of the compound of formula (I); in the form of powder or granules; in the form of a solution or suspension, in an aqueous or nonaqueous fluid; or as an oil-in-water or water-in-oil emulsion. As has already been mentioned, these compositions are prepared by any suitable pharmaceutical method which encompasses a step in which the active substance and the excipient (which may consist of one or more additional components) are brought into contact with each other. In general, the compositions are prepared by uniformly and homogeneously mixing the active substance with a liquid and/or finely divided solid excipient, whereupon the product can be shaped, if so required. For example, a tablet can be prepared by compressing or shaping a powder or granule of the compound, if appropriate together with one or more additional components. Compressed tablets can be prepared by tableting the compound in free-flowing form, such as, for example, a powder or granules, if appropriate as a mixture with a binder, glidant, inert diluent and/or one (or more) surfactant/dispersant, in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound with an inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration encompass lozenges which comprise a compound of formula (I) together with a flavoring, usually sucrose and gum arabic or tragacanth, and pastilles, which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
The invention furthermore also relates to isomer mixtures of formula I and to the pure diastereomers of formula I.
The invention furthermore relates to processes for the preparation of propanolamine derivatives of formula I. 
Shown above is a process for the preparation of compounds of formula I, wherein R4-substituted imines are prepared from amines of type II and aldehydes of type III, R4 having the meaning given for formula I. To this end, for example, the amine II and the aldehyde III are reacted in substance or in a suitable solvent such as ethanol, toluene or acetic acid without or with addition of an acid, for example p-toluenesulfonic acid, at temperatures of 20xc2x0-150xc2x0 C. (a).
Keto compounds of formula VII which are substituted by radicals R1 and R2, where R1 and R2 have the meanings given in formula I, are prepared by processes known from the literature or similarly to such processes. For example, picolin derivatives V are metalated with a suitable base, such as n-butyllithium, and reacted in tetrahydrofuran or another suitable solvent with the corresponding carboxylic acid derivatives VI, for example as carboxylic dialkylamides or carboxylic esters (radical X), at temperatures between xe2x88x9280xc2x0 and 20xc2x0 C. (b).
Compounds of type VII are obtained by reacting imines of type IV and ketones of type VII, in each case substituted with radicals R1,R2 and R4, whereby R1, R2 and R4 have the meaning given for formula I. This reaction can be carried out, for example, by mixing the two compounds in substance, without solvent, and subsequent heating, or in a suitable solvent such as methylene chloride, ethanol, toluene, diglyme or tetradecane at temperatures from 20xc2x0 C. to 150xc2x0 C. (c).
The racemic compounds of type VIII are resolved into the pure diastereomers of types IX and X with the aid of a chiral column (for example using camphanic acid, pentaacetylgluconic acid, camphor-10-sulphonic acid, O-methylmandelic acid or lactic acid), by crystallization, or by chromatography (d).
The keto compounds of type IX or X are reduced in a suitable solvent, such as, for example, methanol, THF or THF/water, using NaBH4 or another suitable reducing agent, at temperatures between xe2x88x9230xc2x0 and +40xc2x0 C. to give hydroxy compounds of type XI, it being possible for these compounds to be substituted by the radicals R1, R2 and R4, R1, R2 and R4 having the meaning given for formula I (e).
The chiral column was cleaved in a suitable solvent such as, for example, methanol, ethanol, THF or THF/water, under basic or acidic conditions, such as, for example, using KOH, NaOH or HCl. The nitro group was subsequently reduced to the amine by processes known from the literature, and compounds of type XII with the radicals R1, R2 and R4 are obtained (f).
The amino compounds of type XII are reacted with the alkyl or acyl radicals R3-Z-Y, where Y represents a leaving group, using methods known from the literature, and compounds of the formula I are obtained (g). If X-Z-Y, where X is a protective group, is employed as the alkyl or acyl radical, intermediates are obtained which can be reacted with further alkyl or acyl radicals R3xe2x80x94Y to give compounds of the formula I (h).
The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal pharmaceuticals for the treatment of disorders of the iipid metabolism, in particular of hyperlipidemia. The compounds of formula I are also suitable for influencing the serum cholesterol level and for the prevention and treatment of arteriosclerotic phenomena. If appropriate, the compounds may also be administered in combination with statins such as, for example, simvastatin, fluvastatin, pravastatin, cerivastatin, lovastatin or atorvastin.